New approaches to define the abnormal signal transduction pathways used by cellular oncogenes in the generation of cancer are needed. This grant will refine and implement a primary genetic screen to identify the cellular components critical for the creation of leukemias by the Bcr-Abl oncogene associated with Philadelphia chromosome positive human leukemias. The screening approach is based on the rescue of a series of partial loss of function mutants of Bcr-Abl, which are tyrosine kinase active but defective in fibroblast and hematopoietic transformation assays. Genes capable of rescuing a strong agar growth phenotype are selected following transfer of cDNA libraries cloned in retroviral vectors into the Bcr-Abl mutant containing cells. The basic concept of the screen has been demonstrated to work, and several novel genes are under investigation. This type of unbiased screen for genes which interact to create the transformed state in mammalian cells should provide insights about the pathogenesis of leukemia and other cancers.